Family History Of Malignancy Research Articles

Should We Offer Universal Germline Genetic Testing to All Patients with Pancreatic Cancer? A Multicenter Study.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a significant percentage of germline pathogenic variants (GPVs). Unlike in the United States, routine universal genetic testing is not performed in Europe. The aim of the study is to evaluate the diagnostic yield of germline genetic testing in all patients with PDAC. Individuals with newly diagnosed PDAC from three Spanish hospitals were enrolled, regardless of family history. Thirteen known susceptibility genes for PDAC were studied using a multigene panel or whole-exome sequencing. One hundred seventy-nine PDAC patients underwent genetic testing. Fourteen (7.8%) had a GPV or likely pathogenic variant In the genes studied: six in ATM, six in BRCA2, one in PALB2, and one in TP53. Of these, seven (50%) did not meet the clinical criteria for genetic study and would have been classified as sporadic PDAC. Presenting with a personal history of any other neoplasm was associated with some GPV, with an odds ratio (OR) of 3.5 (1.1-11.5). A family history of PDAC and breast cancer was also associated with some GPV, with oRs of 3.7 (1.08-13.6) and 8.5 (2.6-26.6), respectively. None of the patients over 60 years without a relevant family history of malignancies presented a GPV associated with PDAC. In our PDAC cohort, a noteworthy number of GPVs were identified, and half of these patients would have been classified as sporadic based solely on clinical criteria. Genetic testing should always be considered, particularly in patients under 60 years or those with a history of other malignancies, especially where economic resources need optimization.

Gastrointestinal pathology in patients presenting with iron deficiency anaemia: A single-centre cross-sectional study

ABSTRACT Background: About a third of the world’s population is estimated to suffer from anaemia, and iron deficiency is expected to account for about half of all anaemia cases. This study was designed to get an estimate of the proportion of patients with iron deficiency anaemia (IDA) who have a significant gastrointestinal (GI) pathology, in particular a GI malignancy, and to identify any risk factors or predictors for the same. Methods: This cross-sectional study was conducted at a hospital in Eastern India. The study population comprised males above the age of 18 and postmenopausal females with IDA, excluding those haemodynamically unstable or with chronic diseases. Data collection included a detailed history, sociodemographic details, dietary habits, GI symptoms, and severity of anaemia. Faecal occult blood tests (OBTs) were conducted, and patients were referred for upper and lower GI endoscopy with biopsies. Results: Out of the 257 patients, 50.97% (n = 131) had a significant GI pathology, and 25.68% (n = 66) had a GI malignancy. Male gender (AOR: 5.203, 95% CI: 1.725–15.698) and a positive stool OBT (AOR: 6.516, 95% CI: 2.255–18.828) were found to be independent risk factors for any GI pathology. Age 40 years or above (AOR: 11.376, 95% CI: 1.199–107.946), loss of appetite (AOR: 15.548, 95% CI: 1.416–170.735), pain abdomen (AOR: 5.566, 95% CI: 1.149–26.953), dysphagia (AOR: 7.945, 95% CI: 1.036–60.915), family history of malignancy (AOR: 46.726, 95% CI: 4.076–535.645), and positive OBT (AOR: 22.430, 95% CI: 3.933–127.915) were found to be independent risk factors of GI malignancy. Conclusions: This study shows that a large proportion of adult males and postmenopausal females presenting with IDA in India have significant GI pathology. Furthermore, a significant proportion of them have GI malignancies. Thus, bidirectional endoscopy should be considered for these patients. Male patients, age >40, those with history of loss of appetite or weight, pain abdomen or dysphagia, positive family history, and positive OBT should be prioritised for the investigation.

Second primary malignancies in women with breast cancer.

Increased screening and treatment advancements have resulted in improved survival rates in women with breast cancer (BC). However, recent data suggests these women have elevated risk of developing a second primary malignancy (SPM) compared to the general population. Limited data exists on factors associated with BC patients developing a SPM. A retrospective review of a prospective single institution database (1990-2016) identified 782 patients with a history of BC. One hundred and ninety-four BC patients developed a SPM. Clinicopathologic and treatment characteristics were analyzed. Of the 194 patients (24.8%) who developed a SPM, 56 (28.9%) BC patients were <50 years old (range: 24-87 years). Two-thirds (64.9%) had at least one first or second degree relative with a malignancy (no relatives-35.1%; ≥1 relative-62.9%). Most patients had invasive ductal carcinoma (n = 117, 60.3%) or ductal carcinoma in situ (n = 39, 20.1%). Twenty-two patients (11.3%) had pathogenic genetic mutations. Mean time to developing a SPM was 8.9 years (range: 4 months-50 years). Eighty (47.6%) patients received chemotherapy with 91 (54.5%) completing radiation. The most common SPMs were breast (22%), melanoma (17.8%), gynecologic (14.1%), colorectal (12.6%), hematologic (8.9%), and sarcoma (6.5%). Most breast tumors were estrogen receptor (ER) (n = 99, 78.0%) or progesterone receptor (PR) positive (n = 87, 73.1%) but not HER2-neu positive (n = 13, 14.0%). Most BC patients who developed a SPM had ER/PR positive tumors and a family history of malignancy, with most <50 years old. Although chemotherapy and radiation increase cancer risk, there were an equal number of patients with SPMs who did or did not receive either treatment. Most SPMs were breast, soft tissue, gynecologic, hematologic, or colorectal. BC patients should be followed closely given an elevated propensity for developing SPMs.

Cancer Screening in Renal Transplant Recipients: Real-World Data.

Multiple international guidelines have endorsed cancer screening in renal transplant patients. This study aimed to describe a series of patients with post-transplant cancer and to report physicians' adherence to cancer screening guidelines. This is a retrospective study of cancer patients who had a history of renal transplant. Charts of patients who were treated at our institution between 2012 and 2023 were reviewed, patients' clinical data were collected. Thirty-nine patients were identified. The most common types of cancer were lymphoma (n = 9, 23%), squamous cell carcinoma (SCC) of the skin (n = 8, 20.5%), and breast (n = 6, 15.4%). The median age at diagnosis was 56.5 years (range: 16.9 - 70.2), family history of malignancy was depicted in 18 (46.2%) cases. Chart review and patients' questionnaire revealed that increased risk of malignancy was discussed in seven (18%) out of 39 recipients (P < 0.001) at time of transplant, and only three (7.7%, P < 0.001) patients were on post-transplant age-matched cancer screening. The increased risk of malignancy is a serious post-transplant complication. Lymphoma and non-melanoma skin cancer were the most common cancers. Most patients were not offered routine cancer screening; it is important to raise awareness among nephrologists and caregivers regarding the risk of post-transplant malignancy.

Study of Epidemiological Patterns and Clinical Profiles of Breast Cancer in Young Patient: A Retrospective Study at Dr. Moewardi Surakarta

Introduction: Breast cancer remains a major health problem and a top priority for biomedical research. The incidence of this aggressive disease is around 1,700,000 new cases each year; This figure shows the low level of efforts to prevent this disease. About 12% of breast cancer cases occur in women aged ≥45 years. Unlike breast cancer in older women and the incidence of metastatic breast cancer has significantly increased in younger women over the past 30 years. Aims: This study aims to identify the characteristics of risk factors on young women with breast cancer patients. Study Design: This study was a retrospective descriptive study, with 182 subjects of young women breast cancer patient at the Department of Oncology, RSUD Dr. Moewardi Surakarta in 2021 - 2023. Place and Duration of Study: Sample: Department of Oncology, RSUD Dr. Moewardi Surakarta in 2021 - 2023. Methodology: This study was a retrospective descriptive study, with 182 subjects of young women breast cancer patient at the Department of Oncology, RSUD Dr. Moewardi Surakarta in 2021 - 2023. The study will be conducted using medical record of the hospital. Results: There were some risk factors that we found. There were young age at diagnosis, nulliparity, family history of malignancies, breastfeeding, hormonal contraception, children count, and age at first pregnancy. Conclusion: This study concludes some risk factors of breast cancer in young women.

HGG-28. THE IMPACT OF CMMRD IN HIGH-GRADE GLIOMA PATIENTS, A RETROSPECTIVE ANALYSIS OF 7 YEARS IN LMIC; AN IRRDC STUDY

Abstract BACKGROUND Constitutional mismatch repair (MMR) deficiency (CMMRD) is a genetic cancer predisposition syndrome presenting among children and young adults. This study is the first to evaluate CMMRD prevalence among high-grade glioma patients in Pakistan, a country with high consanguinity rates. METHODS We reviewed data of patients younger than 18 diagnosed with pediatric high-grade glioma, anaplastic astrocytoma, and diffuse midline glioma with CMMRD testing between 2016 and 2023. Tumor slides of all included cases were prepared and sent to Sick Kids Toronto to review the MMR protein stains via multi-gene panels. RESULTS Forty-five patients were identified (62.3% females); median age of 11. Headache (88.9%) was the most common symptom, followed by vomiting (60%) and seizures (37.8%); median duration of symptoms was two months. Histopathology revealed 73.3% pediatric high-grade glioma, 22.2% Anaplastic Astrocytoma, and 4.4% Diffuse Midline Glioma. Thirty-six patients (80%) had a cerebral tumor, 13.3%, and 6.7% had a posterior fossa and midline tumor, respectively. CMMRD was positive in 15 of 45 patients (33.3%). Eight patients (53.4%) had CMMRD with loss of PMS 2, two (13.3%) had loss of PMS 2 and MLH 1, two (13.3%) had loss of MSH 2, two (13.3%) had loss of MSH 6, and only one patient had loss of MSH 6 and MSH 2. Consanguinity correlated with CMMRD (P=0.045), but family history of malignancy was not significant (P=0.202). One-year overall survival of all patients, with a median follow-up of 4.8 months, was 44.4 %, whereas 1-year overall survival compared to CMMRD was 33.3%, with a median follow-up of 7.2 months (P=0.616) CONCLUSION We found high prevalence of CMMRD among pediatric high-grade glioma patients and patients with consanguinity. The findings of our study emphasize the importance of genetic testing and counseling. Timely accurate diagnosis is essential as decreased response to conventional treatment regimens may increase disease burden.

HGG-19. H3- AND IDH-WILDTYPE DIFFUSE PAEDIATRIC-TYPE HIGH-GRADE GLIOMA WITHMYCN-AMPLIFICATION: AN INDICATION CRITERION FOR LI-FRAUMENI SYNDROME TESTING

Abstract BACKGROUND: In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (5th edition), the introduction of a molecular layer to the integrated diagnosis not only helps to characterize and prognosticate paediatric CNS tumors but the molecular alteration may predict a potential therapeutic option with a targeted agent. Furthermore, certain gene alterations may be a presage of germline alterations or cancer predisposition syndromes, portending significant implications to the index patients and their families. We report a 5-year-old boy diagnosed with non-metastatic left hemispheric H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification, who was subsequently found to have Li-Fraumeni syndrome. He presented with a 3-day history of facial asymmetry, unsteady gait and right sided weakness. There was no family history of malignancy. Initial MRI revealed a restricting and enhancing solid cystic lesion (5.9 x 4.3 x 5.8cm) in the left frontal-temporal-parietal region. Tumor debulking was performed. Histopathological examination by the local pathologist revealed features of high-grade glioma. Second pathology review with next generation sequencing confirmed H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification and TP53 p.Y103* mutation. He was started on focal radiotherapy and oral temozolomide but succumbed to local and metastatic progressive disease. After genetic counselling, his DNA extracted from blood was sent for targeted exome sequencing and germline mutation of TP53 was demonstrated. Cascade screening of the family members were negative of TP53 mutation. Guerrini-Rousseau et al reported that 57% (n=7) of H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification harboured germline TP53 pathogenic variants. This case further highlights the importance of screening of Li-Fraumeni syndrome in patient with H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification even in the absence of a family history.

HGG-01. DURABLE RESPONSE TO IMMUNOTHERAPY IN AN ADOLESCENT PATEINT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY CMMRD AND SYNCHRONOUS THREE PRIMARY MALIGNANCIES

Abstract BACKGROUND Familial Cancer Syndrome FCS is of particular concern in Saudi Arabia due to the high rates of consanguinity. Constitutional mismatch repair deficiency Syndrome (CMMRD) is an autosomal recessive FCS with a wide spectrum of malignancies Caused by Biallelic germline mutations in one of 4 mismatch repair genes (MLH1, PMS2, MSH2, and MSH6). METHODS we report 13 yr. Saudi boy, previously healthy with multiple café-au-lait (CAL) macules, and Consanguineous parents with a positive family history of Malignancy. presented with progressive headache, vomiting, abdominal pain, weight loss, and microcytic anemia. MRI Brain showed a Large left hemispheric necrotic mass, MRI abdomen: Circumferential gastric body wall thickening Distal transverse colon intraluminal polypoid mass, and liver hypodense lesion. He had a Resection of the brain tumor and Upper GI endoscopy + colonoscopy with polypectomy: which showed an Ugly gastric ulcer, and multiple colonic polyps. RESULTS Brain tumor molecular pathology: Gliosarcoma WHO grade 4 with negative IHC expression in PMS2 protein, hypermutant tumor with somatic PMS2 ATRX, TP53, NFI, and PIK3R1 genes mutation. stomach biopsy confirmed invasive gastric adenocarcinoma and Colonic polyp biopsy: Tubulovillous adenoma. Genetic testing Detect pathogenic Biallelic germline PMS2 mutation. He received adjuvant focal Brain radiation therapy 59.4Gy/33 F concurrent with immunotherapy (PD-1) inhibitor Nivolumab. Follow-up Abdominal imaging showed excellent response to immunotherapy with no significant residual lesion. MRI of the brain showed surgical bed multi-cystic lesions with thick nodular enhancement suggestive either of radiation necrosis vs. progressions/pseudoprogression. repeated MRI confirmed further progression of the enhancing surgical cavity lesion which was unresectable. CTLA-4 Inhibitor ipilimumab was added to Nivolumab to optimize therapy. UpToDate our patient is clinically stable on Maintenance Nivolumab with no side effects. CONCLUSION Our case confirms immunotherapy’s efficacy for treating CMMRD-related cancers, which can improve survival while reducing toxicity from less effective conventional therapies.

OA14 Subcutaneous panniculitis-like T-cell lymphoma: a mimic of lupus erythematous panniculitis

Abstract Background/Aims Lupus erythematosus panniculitis (LEP) is a rare variant of cutaneous lupus erythematosus characterised by tender, erythematous subcutaneous nodules or plaques on the face, trunk and proximal extremities. Without treatment, profound lipoatrophy frequently occurs, which often has a devastating psychosocial impact. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous T-cell lymphoma, which may appear in a similar manner. SPTCL initially preferentially infiltrates the subcutaneous adipose tissue and symptoms vary widely depending on the stage of the disease. Early-stage disease presents as painless self-resolving subcutaneous nodules on limbs and trunk. Methods We present the case of a young woman who presented with progressively developing, widespread painful cutaneous lesions, pyrexia of unknown origin and general malaise for one month. She had a history of hurthle cell neoplasm and a strong family history of malignancy. Initial examination revealed 1-2 cm firm, skin-coloured subcutaneous nodules over her lower back, chest and thigh, with groin and axillary lymphadenopathy. Further lesions progressively developed over a three-month period, with lesions turning increasingly erythematous and with associated ulceration. Of note, a significant periorbital lesion appeared, associated with an ipsilateral facial palsy. Results Initial bloods revealed an elevated LDH with cholestatic liver function tests. PET-CT imaging showed an enlarged axillary node with extensive pathology throughout the subcutaneous fat of unknown aetiology. Due to the family history, underlying haematological malignancy and atypical Sweet’s were considered for this unusual presentation. Seropositivity for anti-Ro and ENA, alongside raised angiotensin converting enzyme, broadened the differentials to include LEP, mixed atypical connective tissue disease and cutaneous sarcoid. Notably, complement, myositis panel and creatine kinase were normal. Lupus vulgaris was considered due to high local prevalence and excluded with T-SPOT testing. Histopathological analysis of lesional skin from the upper arm found predominantly subcutaneous infiltrates of atypical lymphoid cells with irregular hyperchromatic nuclei and rimming of individual fat cells. T-cell clonality analysis detected clonal T-cell receptor beta (V-J and D-J) gene rearrangements consistent with SPTCL. Her orbital and cutaneous lesions responded well to six cycles of CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) and the patient returned to functional baseline. Conclusion This case demonstrates the diagnostic difficulties when managing a patient with relapsing remitting panniculitis. Whilst the initial presentation of SPTCL here was classical, with widespread multifocal subcutaneous nodules, the appearance of facial symptoms in SPTCL is rare. Diagnostic uncertainty is frequent in both LEP and SPTCL due to the initial non-specific cutaneous presentation. This case emphasises the importance of clinicopathological correlation for accurate diagnosis. Interestingly, up to 20% of SPTCL patients have concomitant autoimmune diseases, and there is evidence suggesting a potential association between LEP and subcutaneous SPTCL beyond chance, leading some researchers to propose that these two entities exist along a spectrum. Disclosure D. Li: None. L. Spencer: None.

Early cancer screening surveillance in one medical center of China.

Cancer screening aims to detect and treat malignant lesions at an early stage and to prolong patients' lifetime. There is still a lack of effective cancer screening programs in China. We initiated a screening project in 2018 and this study presented the cancer screening status in China. We conducted a cross-sectional study in one cancer-care medical center of China. The screening program included routine blood tests, plasma tumor markers, gastric endoscopy, colonoscopy, ultrasound, and computed tomography (CT) scans. Screening results were presented as sensitivity, specificity and positive predictive values (PPVs). Twenty-three (1.46%) out of 1,576 participants were eventually diagnosed with malignant tumors or high-grade intraepithelial neoplasia (HGIN). A family history of malignancy (78.26% in diagnosed cancer and HGIN vs. 46.36% in the others) was the only statistically significant parameter associated with cancer detection (p = 0.002). None of the common tumor markers were associated with the cancers screened. Except for colonoscopy (50.00%) and ultrasound for renal cancer (66.67%), the sensitivities of most screening methods were 100%. The specificities of all the screening means were above 96%. Most PPVs ranged from 30-60%. We emphasized risk stratification for early cancer screening, such as a family history of cancer. The survey illustrated that gastric endoscopy, colonoscopy, ultrasound, and lung CT for early cancer screening had high specificity, reasonable sensitivity, and PPV. We anticipated this report would motivate larger-sample studies to estimate the risk-to-benefit ratio of cancer screening and urge the establishment of a native Chinese screening project and even guidelines.

Characteristics and Outcomes of Patients with DDX41-Mutated Acute Myeloid Leukemia: A Single-Center Experience

Background: Acute myeloid leukemia (AML) with germline DDX41 mutation is implicated in 2-5% of AML patients (pts). Unlike other genetic predispositions in AML, germline DDX41 mutations are associated with later-onset myeloid malignancies (median age 69 years), making it difficult to distinguish clinically from sporadic AML. Data suggests that pts with germline DDX41-mutated AML have more favorable outcomes compared to sporadic AML. However, data regarding optimal treatment and long-term prognosis remains limited. Methods: Pts treated for AML at The University of Kansas Medical Center between 2015 and 2022 with at least one DDX41 variant were identified via retrospective search. Demographics, disease characteristics, treatments, and vital status were analyzed. DDX41 and other co-occurring mutations included for analysis were pathogenic, likely pathogenic, or variants of uncertain significance. Mutations were considered germline in origin if the variant allele frequency (VAF) exceeded 40% or via search of ClinVar repository in borderline cases (VAF 35-40%, n=2) or if VAF was not reported (n=3). Pts suspected to have germline DDX41 mutations were included in the primary analysis. Results: We identified 42 pts with AML with at least one DDX41 variant. Two cases had donor-derived leukemia after prior related donor allogeneic stem cell transplant (SCT) and two cases only had somatic DDX41 p.R525H mutations. These were excluded from primary analysis. 36 pts had suspected germline DDX41 mutations and were included for analysis. 28 (78%) had DDX41 mutations at diagnosis and 8 were found later with a broader next-generation sequencing (NGS) panel (in 6, after induction and in 2, after relapse). Average age of pts with germline DDX41-mutated AML was 67 years, with 3:1 male predominance. Most had preceding cytopenias, and 12 (33%) had antecedent myelodysplastic syndrome (MDS). Family history of malignancy was common (Table 1). 27 (77%) of the available 35 karyotypes at diagnosis were normal. One patient did not have an available karyotype due to lack of records. 28 pts had testing at diagnosis that included DDX41 in the NGS panel. Of these, 57% (n=16) had two DDX41 mutations, with one germline and one somatic mutation. The most common germline DDX41 mutations were p.M1I (14.3%) and p.D140fs*2 (10.7%), and the most common somatic mutation was p.R525H (39.3%). Other commonly concomitant mutations were in ASXL1 (36.1%), CUX1 (22.2%), and KMT2C (13.9%). Mutations such as NPM1 (5.6%), TP53 (5.6%), and FLT3 (2.8%) were uncommon. Germline testing was performed in 5 (13.9%) pts, confirming germline variants. 39% (n=14) were treated with a 7+3-based regimen (average age 60 years) with a 71% response rate. 36% (n=13) were treated with venetoclax/hypomethylating agent (Ven/HMA) (average age 72 years) with a 69% response rate (Figure 1). Two pts receiving Ven/HMA died during the first cycle (one from myocardial infarction, one from pneumonia). 18 pts (50%) received SCT, and 50% of those (n=9) had a related donor. 33% of related donors (n=3) were tested for a germline DDX41 mutation prior to transplant. At last follow-up, 44% were alive in CR (n=16), 5.5% alive with disease (n=2), 14% deceased in CR (n=5), 25% deceased with disease (n=9), and 11% deceased with unknown status (n=4). Median survival was 12.8 months (average 19.6 months in pts with SCT vs. 8.3 in those without, p = 0.012). 11 pts died from AML (33.3%) or complications (22% infection, 6% bleeding). Two pts with only somatic DDX41 mutations were adverse risk (with ASXL1 mutation) and intermediate risk per 2022 ELN risk stratification, both deceased but in CR at time of death. The adverse-risk patient underwent SCT with unrelated donor (survival 7.3 months). The intermediate-risk patient was re-induced after PIF and died from aortic stenosis (survival 2.2 months). Conclusions: In our cohort of germline DDX41-mutated AML, responses to a 7+3- or Ven/HMA-based regimen were similar. SCT evaluation remains crucial with improved overall survival in pts receiving SCT. Our study highlights the importance of comprehensive genetic testing that includes DDX41 at diagnosis, along with testing of related donors and children of pts with a germline DDX41 mutation due to the impact of positive testing on donor selection and to identify pts at risk of AML. The presence of only somatic DDX41 mutations was rare, and further research is needed on the impact of somatic DDX41 mutations alone.

THU533 Cowden Syndrome: A Rare Disease With A Lasting Impact

Abstract Disclosure: C.S. Hastings: None. S.A. Patrick: None. D. James: None. Introduction: Cowden Syndrome (CS) is a genetic condition caused by an autosomal dominant mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. The prevalence of CS is approximately one in 200,000 and onset is typically in the second decade of life. It is characterized by multiple benign or malignant skin tumors, non-medullary thyroid cancer, breast carcinoma, endometrial carcinoma, gastrointestinal hamartomas, renal cell carcinoma, and/or developmental delay. CS is typically underdiagnosed due to the variety of phenotypic presentations. Case Description: We present a case series of Cowden Syndrome. The first patient was a 51-year-old male with follicular thyroid cancer status post radiation and thyroidectomy, multiple gastrointestinal polyps, trichilemmomas, and an extensive family history of cancer. These factors led to an increased suspicion for CS. The patient underwent genetic testing for PTEN mutations in 2022 and was heterozygous for the c.723dupT pathogenic PTEN mutation as well as p.S598L mutation. The second patient was an 18-year-old female with developmental delay, autoimmune hypothyroidism, multinodular goiter who presented with an increasing number of thyroid nodules on annual thyroid ultrasounds. Her thyroid nodule biopsy revealed follicular and papillary thyroid carcinoma requiring total thyroidectomy. Her mother had a known history of CS. Genetic testing revealed she was heterozygous for the p.S1701 pathogenic mutation in the PTEN gene. Diagnosis of CS involves a combination of family history, presence of mucocutaneous lesions, and either thyroid, breast, or endometrial carcinoma. Given the higher likelihood of cancers in these patients, routine screening for thyroid, breast, kidney, and colon cancers should begin at an earlier age. Treatment includes topical agents such as fluorouracil or excision surgery for skin lesions. Treatment of malignancy is similar to sporadic counterparts and involves systemic immunosuppressants, chemotherapy, or surgery. Conclusion: Cowden Syndrome is a rare genetic condition resulting in tumors in a variety of organ systems, placing patients at a higher risk of malignancy. A strong family history of malignancy, as well as skin, breast, GI, or thyroid findings should prompt further investigation. Collaboration between dermatology, oncology, gastroenterology, endocrinology, and neurology is essential for successful treatment. Routine screening for these patients includes thyroid studies every 3-4 months, thyroid ultrasound yearly, colonoscopy every two years, and renal CT or MRI yearly. Early diagnosis of the condition is pivotal for close cancer surveillance and management. Presentation: Thursday, June 15, 2023

Characterization of de novo malignancy after orthotopic heart transplantation: single-centre outcomes over 20 years.

Malignancy is the leading cause of late mortality after orthotopic heart transplantation (OHT), and the burden of post-transplantation cancer is expected to rise in proportion to increased case volume following the 2018 heart allocation score change. In this report, we evaluated factors associated with de novo malignancy after OHT with a focus on skin and solid organ cancers. Patients who underwent OHT at our institution between 1999 and 2018 were retrospectively reviewed (n = 488). Terminal outcomes of death and development of skin and/or solid organ malignancy were assessed as competing risks. Fine-Gray subdistribution hazards regression was used to evaluate the association between perioperative patient and donor characteristics and late-term malignancy outcomes. By 1, 5 and 10 years, an estimated 2%, 17% and 27% of patients developed skin malignancy, while 1%, 5% and 12% of patients developed solid organ malignancy. On multivariable Fine-Gray regression, age [1.05 (1.03-1.08); P < 0.001], government payer insurance [1.77 (1.20-2.59); P = 0.006], family history of malignancy [1.66 (1.15-2.38); P = 0.007] and metformin use [1.73 (1.15-2.59); P = 0.008] were associated with increased risk of melanoma and basal or squamous cell carcinoma. Age [1.08 (1.04-1.12); P < 0.001] and family history of malignancy [2.55 (1.43-4.56); P = 0.002] were associated with an increased risk of solid organ cancer, most commonly prostate and lung cancer. Vigilant cancer and immunosuppression surveillance is warranted in OHT recipients at late-term follow-up. The cumulative incidence of skin and solid organ malignancies increases temporally after transplantation, and key risk factors for the development of post-OHT malignancy warrant identification and routine monitoring.

Assessment of focal liver lesions in non-cirrhotic liver – expert opinion statement by the Swiss Association for the Study of the Liver and the Swiss Society of Gastroenterology

Focal liver lesions are common, with a prevalence up to 20%. The lesions must be evaluated in context of risk factors associated with malignancy. Risk factors include age &gt;40 years, known current or past malignancy, presence of liver cirrhosis or chronic liver disease (i.e. suspected by elevated liver elastography measurement ≥8 kPa or FIB-4 score ≥1.3), unintentional weight loss, fever or night sweats, newly detected focal liver lesions, documented growth of focal liver lesions, current or past use of androgens (e.g. testosterone, oxymetholone, danazol), increased serum tumour markers (i.e. alpha-fetoprotein, carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA]) and family history of malignancy. In patients without risk factors of malignancy, regional (non-)fatty changes, simple liver cysts and typical haemangiomas can be diagnosed by conventional ultrasound (without contrast). Conventional ultrasound Doppler is recommended to rule out vascular malformations such as portosystemic shunts. In all other cases of focal liver lesions, contrast-enhanced imaging is indicated for differentiation in benign and malignant dignity. Contrast-enhanced ultrasound (CEUS) as a first diagnostic step and contrast-enhanced magnetic resonance imaging (MRI) are accurate tests to diagnose haemangioma and focal nodular hyperplasia. Hepatocellular adenoma is diagnosed by contrast-enhanced MRI and/or histology. “Wash out” on CEUS is highly suspicious for a malignant focal liver lesion. Additional investigations aimed at identifying the primary tumour, as well as staging-computed tomography, MRI and/or histology may be necessary and should be decided on a case-by-case basis. A biopsy of focal liver lesions is indicated in cases of unclear dignity, malignant aspect and focal liver lesions of unclear origin as well as for guiding surgical and oncological management.

Early-Onset Virilization May Rarely be Due to an Adrenocortical Neoplasm

Background: Adrenocortical tumors are rare neoplasms of childhood; most of which are functional in childhood, producing excess hormones. Virilization, precocious puberty, and Cushing's syndrome are common presenting features. Clinical Description: A 6-year-8-month-old girl presented with features of virilization, which started appearing at 2 ½ years of age. The mother gave a history of progressive enlargement of the clitoris with the development of pubic, axillary, and facial hair over the years. There was no history of perinatal complications, features of adrenal insufficiency, atypical external genitalia at birth, or family history of malignancy. On examination, she had features of heterosexual peripheral precocious puberty. The hormonal investigation was suggestive of cortisol and androgen excess. Radiologically, she had an adrenal tumor appearing like adrenocortical carcinoma (ACC)-large size, high noncontrast Hounsfield units, and poor washout. Management and Outcome: As virilization was not present since birth and there was no evidence of adrenal insufficiency, therefore, the possibility of congenital adrenal hyperplasia was unlikely. Investigations revealed that the testosterone levels were much higher than other adrenal androgen precursors like dehydroepiandrosterone sulfate. This was a clinical clue to the well-differentiated and benign nature of the tumor although radiologically it appeared like ACC. The child underwent en bloc resection of the mass, and histopathology was suggestive of a benign adrenocortical adenoma. Seven days after surgery, the serum testosterone had dropped substantially. Conclusion: This case creates awareness about the possibility of an adrenocortical neoplasm in a child with early-onset virilization, which can be diagnosed correctly by following a step-wise, logical sequence of investigations.

Nasljedni karcinom dojke i jajnika - iskustva Kliničkog bolničkog centra Split

Aim: To investigate the clinical and pathohistological tumor characteristics, treatment, and treatment outcomes in patients with hereditary breast and ovarian cancer who were diagnosed, treated, and monitored at the University Hospital of Split from October 1999 to April 2021. Methods: The data were collected retrospectively from the medical history of 15 patients. They included the patient’s age at diagnosis, family history of malignancies, histological subtype, grade, breast cancer immunophenotype, stage of disease, status and types of BRCA mutations, type of surgical and oncological treatment, the specifics of metachronous bilateral breast cancers, the specifics of synchronous breast and ovarian cancers, and the outcome of treatment through overall survival (OS). Results: The median age of patients at the time of diagnosis of breast cancer was 53 years, and for ovarian cancer it was 56 years. A positive family history was confirmed in 13 patients (87%). All ovarian cancer patients had a high-grade serous histologic type, most often diagnosed in FIGO stages III and IV. Breast cancers were most commonly diagnosed in stages IA and IIA, with equally represented triple-negative and luminal immunophenotypes. The most common mutation was BRCA1 c.5266dup. The median OS of our patients was not reached. Conclusion: The clinical features of patients, pathohistological characteristics of tumors, and treatment outcomes in our study population are comparable with reports in the literature, respecting the specifics of different nations and race

DP08 Next-generation sequencing: the future for malignant melanoma diagnostic precision? A case of a BAP1 mutation

Abstract A 48-year-old man presented to the hand surgeons with a 5-year history of a subcutaneous swelling on his right wrist, associated with paraesthesia and pain, initially thought to be a benign ganglion. Excision biopsy of the lesion on histology revealed an encapsulated pleomorphic tumour attached to a nerve, thought to represent a sarcoma. Immunohistochemistry showed a positive reaction to S100, SOX10, calretinin and synaptophysin. Ki67 showed a 20% proliferation index. Multiple pathology opinions were sought, and further testing was performed at a specialist genomic laboratory. Detailed questioning regarding family history of malignancy revealed that the patient’s mother had died from metastatic uveal melanoma, a maternal aunt had died of a brain tumour and his maternal grandmother had lung cancer. Pan-cancer gene panel DNA next-generation sequencing showed a BAP1 mutation with a very high variant allele fraction, suggestive of germline inheritance. Given the clinical history, morphology, immunoprofile and DNA result, a favoured diagnosis of metastatic malignant melanoma with a BAP1 mutation was made. The patient was referred to the specialist skin cancer multidisciplinary team meeting and reviewed by the dermatology team. Full skin check examination revealed two long-standing atypical naevi (&amp;gt; 10 years), one on the left forearm and another on his back, and these were excised urgently. Histology of the back lesion showed a polypoid melanocytic tumour comprising large epithelioid melanocytes with mild-to-moderate nuclear pleomorphism, multinucleated cells and intranuclear inclusions. This was in keeping with a pT4a nodular malignant melanoma with 7-mm Breslow thickness, associated with BAP1-inactivated syndrome. Histology of the left forearm lesion was consistent with a combined BAP1-inactivated melanocytoma, otherwise known as a ‘BAPoma’. An ophthalmology review did not identify a primary uveal melanoma. Staging scans of his chest, abdomen and pelvis and magnetic resonance imaging of his head showed no evidence of metastatic disease. The patient was referred for genetics counselling, wide local excision of the melanoma on his back, for consideration of adjuvant therapy with oncology and long-term follow-up with dermatology. BAP1 tumour predisposition syndrome is a newly recognized cancer syndrome that predisposes the patient to uveal melanoma, malignant mesothelioma, renal cell carcinoma, cutaneous melanomas and a range of other cancers (Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol 2018; 30:102–9). BAP1-related cancers tend to occur earlier in life and are more aggressive. Our case highlights the need for early identification of germline mutations through sequencing to improve outcomes and treatment-related morbidity by early diagnosis in these rare cancer syndromes.

P-738 Attitude of BRCA1/2 mutation carriers towards fertility preservation, family planning and preimplantation genetic testing (PGT) for the next-generation primary prevention of breast and ovarian cancer

Abstract Study question What is BRCA1/2 mutation carriers' attitude toward preimplantation genetic testing (PGT) in attempt to prevent their offspring burden that comes with a known mutation status? Summary answer Less than ten percent of BRCA1/2 mutation carriers chose to perform PGT to avoid the birth of a child who is also a carrier. What is known already BRCA1/2 mutation carriers encounter many dilemmas during their life such as whether to undergo fertility preservation, when and how to plan their family, when to undergo risk reduction surgeries and whether to perform PGT for the selection of non-carrier embryos. Awareness and attitudes toward PGT are different across countries and has been shown to be associated with the degree of suffering from the knowledge of being a carrier, from personal or familial BRCA1/2 associated breast and ovarian cancer. Study design, size, duration This cross-sectional study was conducted by the distribution of an anonymous questionnaire in BRCA1/2 carriers social media platforms and clinics from August 2022 to January 2023. Participants/materials, setting, methods Female respondents of the questionnaire with a positive germline BRCA1/2 mutation at any age or marital status. Main results and the role of chance The questionnaire was completed by 494 BRCA1/2 mutation carriers. The median age of responders was 43 years old (range 22-79), 90% of them Ashkenazi (full or partial) Jewish ethnicy. 63% of patients were carriers of the BRCA1 mutation, while 37% were carriers of the BRCA2 mutation. 76% of patients became aware of their mutation status following a family history of malignancy. 35% of responders did not have children at the time of mutation discovery. 15% of patients had a fertility issue regardless of their BRCA mutation status. Following mutation discovery, 38% of responders changed their family planning, mostly choosing to have children earlier in life or to have less children than planned. 28% of BRCA carriers have been discussed about their option for fertility preservation and 11% underwent the oocyte or embryo vitrification. 45% of BRCA carriers admitted they have discussed the option of PGT and only 8% underwent the in vitro fertilization and preimplantation genetic testing to select non- carrier embryos. 14% of responders were firmly against the option of PGT. The need for fertility treatment regardless of the mutation status did not significantly change the PGT performance rates (p = 0.09). Limitations, reasons for caution This study’s limitations mostly stem from online distribution of the questionnaire. Responders' bias may cause an overestimation of treatment rates as responders may be those who encounter their physicians more frequently and maintain their follow-up as recommended. Nevertheless, the study represents 494 BRCA1/2 carriers and portrays an important healthcare view. Wider implications of the findings Physicians should discuss PGT, family planning and fertility preservation options with BRCA1/2 carriers enabling a personal based decision. It seems that among BRCA carriers, known mutation status largely affects family planning and to a much lesser degree affects fertility preservation and performance of PGT to select non carrier offsprings. Trial registration number Not applicable

Extraskeletal osteosarcoma of primary retroperitoneal origin.

A 53-year-old man with a history of ischaemic heart disease presented to his general practitioner with a 6-week history of right-sided abdominal discomfort, associated with worsening constipation and early satiety. He denied weight loss and pain or swelling in the extremities. No family history of malignancy was reported. On examination, we noted a large, hard mass in the right iliac fossa, with no clinical features of ascites.

Survival outcomes of BRCA1/BRCA2 mutated breast cancers: Study from a tertiary care cancer centre in India.

e22546 Background: There exists a discrepancy amongst various studies over the years on survival outcomes of BRCA (Breast cancer susceptibility gene) mutated breast cancers. Prevalence of BRCA mutation varies from 10 to 18% among Indian population and there is a paucity of data on the survival outcomes of this population. Methods: This ambispective observational study assessed the survival outcomes of 71 BRCA mutated breast cancer patients, treated with uniform protocol at AIIMS New Delhi between January 2014 to December 2022, using survival analysis and cox regression methods. Results: Amongst the 71 patients, BRCA1 and BRCA2 mutated cases were 52 (73.2%) and 19 (26.8%) respectively. The median age was 39 years (24-63 years) in both the groups. Positive family history for malignancy (BRCA1- 69.2% vs BRCA2- 36.8%) and incidence of Triple negative histology (BRCA1-82.7% VS 36.8%) were more commonly associated with BRCA1 positivity. Eight patients (11.3%) had synchronous cancer, most common being a contralateral breast primary. 4 patients (5.6%) developed metachronous cancer. Eighty percent of patients were premenopausal at presentation. There was no difference in stage at presentation, incidence of synchronous and metachronous cancers across both the groups. Of 71 patients, 18 (25%) and 17 (24%) patients underwent risk reducing mastectomy and risk reducing oophorectomy respectively. Thirty five (49.3%) presented with stage I &amp; II disease, while 28 (34.4%) and 7 (9.9%) presented with stage III and metastatic disease respectively. Forty seven patients (67.1%) received neoadjuvant chemotherapy with pathologic complete response rate of 42.5% which was uniform among both the groups. Over the study period, 10 (14.1%) patients had disease relapse with 7 (70%) being metastatic and 3 patients died of the disease. With a median follow up of 36.9 months, 3-year disease free survival (DFS) was 84.2% (BRCA1: 81.1% vs BRCA2: 93.1%) and overall survival (OS) was 94.7% for both groups. Median DFS and OS were not achieved. BRCA type, receptor status, age and menopausal status were not predictors of survival in our study. Conclusions: In our study population of BRCA1/BRCA2 mutated breast cancer, survival outcomes were comparable to historical cohorts of Indian breast cancer patients. Thus, BRCA mutation positivity doesn’t seem to have any prognostic significance in breast cancer outcome.